The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to sort out changes due to aging and from those due to disease or other causes. We investigated the prospective association of hearing loss with incident all-cause dementia and Alzheimers disease in participants in the Baltimore Longitudinal Study of Aging (BLSA). Data included 639 individuals who underwent audiometric testing and were dementia free in 1990 to 1994. Hearing loss was defined by a pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear (normal, <25 dB n = 455;mild loss, 25-40 dB n = 125;moderate loss, 41-70 dB n = 53;and severe loss, >70 dB n = 6). Cox proportional hazards models were used to model time to incident dementia according to severity of hearing loss and were adjusted for age, sex, race, education, diabetes mellitus, smoking, and hypertension. During a median follow-up of 11.9 years, 58 cases of incident all-cause dementia were diagnosed, of which 37 cases were AD. The risk of incident all-cause dementia increased log linearly with the severity of baseline hearing loss (1.27 per 10-dB loss;95% confidence interval, 1.06-1.50). Compared with normal hearing, the hazard ratio (95% confidence interval) for incident all-cause dementia was 1.89 (1.00-3.58) for mild hearing loss, 3.00 (1.43-6.30) for moderate hearing loss, and 4.94 (1.09-22.40) for severe hearing loss. The risk of incident AD also increased with baseline hearing loss (1.20 per 10 dB of hearing loss) but with a wider confidence interval (0.94-1.53). Hearing loss was independently associated with incident all-cause dementia after adjustment for sex, age, race, education, diabetes, smoking, and hypertension, and our findings were robust to multiple sensitivity analyses. The risk of all-cause dementia increased log linearly with hearing loss severity, and for individuals older than 60 years in our cohort, more than one-third of the risk of incident all-cause dementia was associated with hearing loss. Using autopsy samples, we investigated the role of activity-dependent modulation of neuronal gene expression in promoting neuronal survival and plasticity, and neuronal network activity perturbation in aging and Alzheimer's disease (AD). We showed that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca(2+) signaling;alterations in pathways involved in lipid metabolism and energy management were also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca(2+)-mediated degeneration.